1. Field of the Invention
The present invention relates to a method for determining the influence of a test substance on the heart activity of a vertebrate, in particular on the interval between ventricular depolarization and repolarization.
2. Related Prior Art
It has long been known that many substances with which animals and humans come into contact may have an influence on heart activity. These substances can generally be environmental factors which are absorbed by breathing or through the skin or in food, or intentionally administered pharmaceutical substances and cosmetic products. In the context of the present application, these substances are generally referred to as “substances” or “test substances”.
To protect livestock animals, domestic animals and, in particular, human beings from the harmful or damaging influence of such substances, not only are the toxicity and the desired action of these substances tested, but increasingly also their undesired influence on heart activity, before said substances are released for use.
In addition, however, there is also a need to test substances already in use, in particular approved medicaments or those being used in clinical trials, in order to ascertain their influence on heart activity. In the case of medicines in particular, undesired side effects on heart rate activity often arise which are not detected in the context of the clinical trials conducted for approval of these medicines or in the preliminary stages of such clinical trials. This leads to a potential danger to persons participating in clinical studies in particular, and to all patients in general.
Such undesired side effects may only become apparent as harmful for example after pro-longed administration, in combination with other substances, or in the presence of risk factors, for example hypokalemia, or structural heart disease, so that they cannot be reliably detected either in the preliminary phases of or during the conduct of clinical trials and studies.
In the context of clinical trials and studies, the influence of substances on heart activity can be determined by what is called electrocardiography, that is to say by recording the ventricular stimulus conduction in the heart in the course of heart activity, the time course being plotted as a tracing, a so-called electrocardiogram. The tracings represent the sum of the intensities and directions of the electrical potentials in the individual myocardial and nerve fibres, and they are recorded by leads assigned in different spatial configurations with respect to the heart, for example on the extremities.
An electrocardiogram is divided into different elements which can be assigned to different physiological processes. The P wave records the excitation of the atrium, and it is followed by the isoelectric PQ segment which records the conduction time of the excitation to the ventricles. The QRS complex corresponds to the ventricular excitation; this is followed by the ST segment, which in turn is followed by the T wave which corresponds to the ventricular repolarization. From the changes in the segment duration and the shape of the elements in the recorded tracings, it is possible to draw important conclusions regarding the heart.
An important variable here is the QT interval, that is to say the time from the start of the QRS complex to the end of the T wave, reflecting the overall electrical action of the ventricle. This QT interval is therefore a measure of the duration of the ventricular depolarization and repolarization.
It is known that a change in the QT interval leads to increased health risks, particularly as a result of rhythm disturbances. For example, a prolongation of the QT interval leads to an increased risk of ventricular tachycardia and fatal arrhythmia. This change in the QT interval may be congenital or may have been acquired as a result of disease or ingestion of harmful substances.
Numerous medicaments are known with which a desired change in the QT interval can be effected in order to counteract pathological changes. On the other hand, there are many substances which have an undesired influence on the QT interval which in many cases goes unrecognized or cannot be detected in conventional clinical studies.
However, even if the influence of substances on heart activity and the associated side effects, for example QT prolongation, could be reliably and conclusively determined with the aid of electrocardiography in the context of clinical studies, the conduct of such studies nevertheless constitutes an unacceptable risk to those participating in these studies and investigations. Quite apart from the ethical problems surrounding the conduct of tests on animals, these tests in the final analysis are not purposeful because there is a limit to the extent to which data from animal tests can be transposed to humans.
In addition, not only would carrying out clinical studies or animal experiments to test the many substances already on the market for their influence on heart activity be associated with high costs, it would also take a considerable time before each particular study was concluded.